Hypoxia determines survival outcomes of bacterial infection through HIF-1α–dependent reprogramming of leukocyte metabolism

A. A. Roger Thompson, Rebecca S. Dickinson, Fiona Murphy, John P. Thomson, Helen M. Marriott, Adriana Tavares, Joseph Willson, Lynne Williams, Amy Lewis, Ananda Mirchandani, Patricia Dos Santos Coelho, Catherine Doherty, Eilise Ryan, Emily Watts, Nicholas M. Morton, Shareen Forbes, Roland H. Stimson, Abdul G. Hameed, Nadine Arnold, Julie A. PrestonAllan Lawrie, Veronica Finisguerra, Massimiliano Mazzone, Pranvera Sadiku, Jermaine Goveia, Federico Taverna, Peter Carmeliet, Simon J. Foster, Edwin R. Chilvers, Andrew S. Cowburn, David H. Dockrell, Randall S. Johnson, Richard R. Meehan, Moira K. B. Whyte, Sarah R. Walmsley

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia and bacterial infection frequently coexist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both Staphylococcus aureus and Streptococcus pneumoniae infections rapidly induced progressive neutrophil-mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, before infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of hypoxia-inducible factor (HIF) pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilization, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus, we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes after bacterial infection through suppression of HIF-1α and neutrophil metabolism. In the context of systemic or tissue hypoxia, therapies that target the host response could improve infection-associated morbidity and mortality.
Original languageEnglish
Article numbereaal2861
JournalScience Immunology
Volume2
Issue number8
Early online date10 Feb 2017
DOIs
Publication statusPublished - 24 Feb 2017

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